Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Male Mice Consuming Alcohol Attenuates Glycolysis

Yann Ehinger, Sophie Laguesse, Khanhky Phamluong, Alexandra Salvi, Yoshitaka J. Sei, Zachary W. Hoisington, Drishti Soneja, Sowmya Gunasekaran, Ken Nakamura and Dorit Ron ()
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Yann Ehinger: San Francisco
Sophie Laguesse: San Francisco
Khanhky Phamluong: San Francisco
Alexandra Salvi: San Francisco
Yoshitaka J. Sei: San Francisco
Zachary W. Hoisington: San Francisco
Drishti Soneja: San Francisco
Sowmya Gunasekaran: San Francisco
Ken Nakamura: San Francisco
Dorit Ron: San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use disorder (AUD). The mechanisms underlying alcohol-mediated mTORC1-dependent neuroadaptations that drive AUD are not well understood. We report that activation of mTORC1 in the nucleus accumbens (NAc) D1 neurons of male mice consuming alcohol results in paradoxical mTORC1-dependent repression of translation of transcripts, including Aldolase A, an essential enzyme in glycolysis. We further show that mTORC1-dependent Aldolase A translation repression in D1 neurons is mediated through upregulation of miR-34a-5p expression. Alcohol-mediated mTORC1 repression of Aldolase A translation in D1 neurons inhibits glycolysis in the NAc. Finally, we report that overexpression of miR-34a-5p in D1 NAc neurons increases, whereas systemic administration of L-lactate, the final product of glycolysis, attenuates excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.

Date: 2025
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DOI: 10.1038/s41467-025-60337-9

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